The present invention relates to manufacturing methods of artificial organs including microporous membranes for treating body fluid. The microporous membranes, which are formed of hydrophobic materials, have portions coated with a fat-soluble modifier. More particularly, the present invention pertains to manufacturing methods of artificial organs, such as, dialyzers, oxygenators, and plasma separation apparatus. Such artificial organs have excellent biocompatibility by inhibiting activation of blood constituents such as leukocytes, and platelets.
Moreover, the present invention relates to hollow fiber membranes, and dialyzers of hollow fiber membrane type, which are each excellent in removal of substances having middle molecular-weight. More particularly, the present invention pertains to hollow fiber membranes, and dialyzers of hollow fiber membrane type, which are each biocompatible by inhibiting activation of blood constituents such as leukocytes, and platelets.
Generally, synthetic macromolecular membranes have been widely used as dialysis membranes, and blood constituent separation membranes to be used in artificial organs, such as dialyzers, and plasma separators. However, when a patient undergoes a blood dialysis treatment with a dialyzer, a frequent extracorporeal circulation is needed. This often brings about complications caused by activation of blood constituents, and casts a serious problem to the patient. Particularly when patients who have taken a dialysis treatment for a long period of time, lowering of anti-oxidation of blood constituents, and high content of lipid peroxide in blood are observed in these patients. Such patients are in many cases affected with arterial sclerosis.
In order to solve the problems, an artificial organ having a dialysis membrane with a surface coated with vitamin E, is proposed (JP-B-62-41738). In this case, the vitamin E possesses experts various physiological activities, such as intracorporeal anti-oxidation, stabilization of biomembranes, and inhibition of platelet coagulation. Highly unsaturated fatty acids such as eicosapentaenoic acid are also expected to exert antithrombotic activity and to improve hyperlipemia.
The above mentioned instances are concerned with a technology to treat a surface of a portion of body fluid treatment membrane, which contacts body fluid. On the other hand, another technology to increase hydrophobic properties of a portion of body fluid treatment membrane, which does not contact body fluid, has also been known. The membrane according to the latter technology adsorbs hydrophobic substances present in a dialysis liquid effectively so that invasion of those hydrophobic substances into body fluid is prevented.
However, when fat-soluble substances such as vitamin E are applied as a modifier for artificial organ materials, which are hydrophilic, the binding strength is weak between a fat-soluble substance and an artificial organ material. This causes a problem that the fat-soluble substance is peeled off the artificial organ material or is eluted.
Solubility parameter xcex4 is known as an indicator of hydrophilicity of a material. The higher the value of xcex4 is, the higher the hydrophilicity of the material is. Blood was circulated for 30 minutes in an artificial organ formed by a hydrophilic material, i.e., regenerated cellulose (xcex4=15.65 (cal/cm3)xc2xd) having a surface coated with vitamin E. It was observed that about 90% of vitamin E on the surface of the regenerated cellulose has been eluted into blood.
A hydrophobic material, for example, having a xcex4 value of at most 13 (cal/cm3)xc2xd is used and coated with vitamin E. The whole area of the membrane is non-selectively coated with vitamin E, as far as a vitamin E solution is applied to the membrane according to a method described in JP-B-62-41738. In the above method, a CFC (chlorflourocarbon), n-hexane, or an alcohol is employed as a solvent, since all of them are inert to a dialysis membrane and dissolve vitamin E. These solvents easily enter pores of hydrophobic porous membrane. Therefore, vitamin E is dispersed all over the inner, middle, and outer surfaces of the membrane and deposited on these portions non-selectively. It is difficult to control the quantity of vitamin E to be deposited on the surfaces of the membrane, since vitamin E is deposited even on an area, which does not contact body fluid. Moreover, ability of the membrane to treat fluid such as body fluid is decreased, since the membrane is coated with vitamin E all over the surface and is changed to be more hydrophobic.
Generally, substances with molecular weight of about 100 have been removed by dialysis treatments. However, a recent dialysis treatment has enabled to remove not only these substances, but also so-called uremic middle molecular-weight substances with a molecular weight of between 100 and 5,000, and even xcex22-microglobulin with a molecular weight of 11,800 (xcex22-MG). Thus, it is now possible for a patient to improve complications caused by a long dialysis treatment. Manufacture of a larger pore-sized membrane than that ordinarily used by utilizing synthetic polymers such as polysulfones and polyamides has been under study (EP 168783, EP 82433). The membrane may remove larger molecular-weight substances by allowing them to pass through the larger pore-sized membrane. However, the larger pore-sized membrane has similar problems as those of an ordinary pore-sized membrane, as described above, if the larger pore-sized membrane is put to use in fabricating artificial organs to treat body fluid.
Accordingly, it is an objective of the present invention to solve the above mentioned problems by providing a manufacturing method of an artificial organ having microporous body fluid treatment membranes, which are made of a hydrophobic material and include a portion coated with a fat-soluble modifier. Another objective of the present invention is to provide a manufacturing method of an artificial organ such as a dialyzer, an oxygenator, or a plasma separation apparatus. The artificial organ inhibits activation of blood constituents such as leukocytes and platelets, and has excellent biocompatibility. A further objective of the present invention is to provide a hollow fiber membrane and a blood dialysis apparatus having the hollow fiber membranes. The hollow fiber membrane has excellent properties in removing substances with middle molecular-weight and has a concentrated fat-soluble modifier on a surface, which may contact body fluid. To achieve the above objectives, the present invention provides the following:
(1) A manufacturing method of an artificial organ comprises a microporous body fluid treatment membrane, which is formed of a material with a solubility parameter xcex4 of not more than 13 (cal/cm3)xc2xd and has a portion coated with a fat-soluble modifier. The manufacturing further comprises the steps of:
filling micropores of the body fluid treatment membrane with a filling solution, which has no or little solubility with a fat-soluble modifier solution; and
coating a portion of the membrane to be coated with a fat-soluble modifier by contacting the fat-soluble modifier solution;
(2) The manufacturing method according to the method of (1), further comprising the step of removing the filling solution between the filling process and the coating process, wherein the filling solution is present on a surface of the portion of the membrane to be coated with the fat-soluble modifier;
(3) The manufacturing method according to the method of (1) or (2), wherein the coating process is to hold the fat-soluble modifier solution on the body fluid treatment membrane;
(4) The manufacturing method according to the method of any one of (1) to (3), wherein the fat-soluble modifier is vitamin
(5) The manufacturing method according to the method of any one of (1) to (4), wherein the filling solution is water;
(6) The manufacturing method according to the method of any one of (1) to (5), wherein a portion to be coated with the fat-soluble modifier is a surface portion of the body fluid treatment membrane, which may contact body fluid;
(7) The manufacturing method according to the method of any one of (1) to (5), wherein the portion to be coated with the fat-soluble modifier is a surface portion of the body fluid treatment membrane, which may not contact body fluid;
(8) A hollow fiber membrane comprising a microporous hollow fiber membrane having a surface, which may contact body fluid, and which includes a fat-soluble modifier, wherein
not less than 50 wt % of fat-soluble modifier included in the hollow fiber membrane is held on a surface, which may contact body fluid; and
sieve coefficients measured by dextrans are:
not more than 0.4 when a dextran with a molecular weight of 100,000 is employed; and
not less than 0.5 when another dextran with a molecular weight of 10,000 is employed;
(9) The hollow fiber membrane according to the membrane of (8), wherein the hollow fiber membrane is formed of a synthetic polymer substrate having a solubility parameter xcex4 of not more than 13 (cal/cm3)xc2xd;
(10) The hollow fiber membrane according to the membrane of (8) or (9), wherein the fat-soluble modifier is a fat-soluble vitamin;
(11) A dialyzer comprising a hollow fiber membrane, a body fluid passage, and a dialysis fluid passage, wherein a body fluid flowing in said body fluid passage contacts a dialysis fluid flowing in said dialysis fluid passage through said membrane so that a spodogenous substance in said body fluid is transferred into said dialysis fluid and removed, wherein said hollow fiber membrane is the membrane of any one of (8) to (10); and
(12) The dialyzer of hollow fiber membrane type according to the dialyzer of (11), wherein the artificial organ is obtained by the manufacturing method of the artificial organ according to the method of any one of (1) to (6).